Immunomodulators

Question 1

Monoclonal Antibodies (mAb)

1. What are they?
2. How are they made?

Answer 1

mAb

1. Monospecific antibodies made from B-cell clones; specific to one epitope/antigen
   
   • Work by inducing ADCC (cards on ADCC later)
2. Derives from a single B cell, fused with a multiple myeloma tumor cell
   • Resultant hybrid line can grow forever in culture like its tumor parent, but make the specific antibody of its B cell parent.

Question 2

mAb’s as antiinflamatorry agents

1. Name the 2 examples that are used as inflamatorry agents
2. What factors or receptors do they act on?

Answer 2

1. Infliximab - chimeric Ab against TNFα → approved for a lot of inflammatory diseases
2. Tocilizumab - Anti IL-6 receptor → approved for RA (inflammation)
   
   • TGF + IL-6 = aggressive T cells

Question 3

1. What are the 4 types of mAb’s?
2. List them in order of least preferable (likely to be recognized by your immune system) to most preferable (least likely to be recognized by immune system)

Answer 3

1. Murine - Least preferable; totally mouse antibody
2. Chimeric - engineered at the DNA level to have the mouse VL and VH domains, but have human C domains
3. Humanized - only the CDR’s of the V domains are from the mouse.
4. Human - Most preferable; completely human antibody

Recall: the more similar you are to human antibody the less likely you recognize the mAb as foreign

Question 4

What are the drug classes for each of the 4 types of mAbs?

Answer 4

1. Murine: [-o**mab] “**oh we discovered something”
2. Chimeric: [-ximab] “We crossed (x) it with human)
3. Humanized: [-zumab] “z are close to human (prounonced Ze, like we)”
4. Human: [-umab] “This is made of u”

Question 5

What is a Natural Killer (NK) cell?

Answer 5

• Large granular lymphocytes (LGL) which make up 5-10% of lymphocytic cells.
• Killers with mechanisms VERY similar to those of CTL, but they do not have rearranged V(D)J genes and are not thymic-derived.
• Part of the innate immune system.
  
  • Attack virally-infected cells or many tumors
• They have a second cytotoxic killing mechanism → ADCC (Antibody-dependent cell-mediated cytotoxicity)

Question 6

Describe Antibody Dependent Cell-mediated Cytotoxicity (ADCC)

Answer 6

• A cell, e.g. tumor cell is recognized by antibodies (i.e. IgG), but are not able to kill it
  
  • NK cells recognize the Fc portion of the bound Ab and bind to it acting in a similar manner as a CTL
    
    • NK then induces cell apoptosis

*Without the bound Ab’s the NK cells don’t kill the tumor cell

*New therapeutic mAb’s (used to modulate the immune response, or treat cancer) work by triggering ADCC

Question 7

Describe CAR T-cell therapy as it relates to cancer treatment?

Answer 7

• T cells are removed from a cancer patient and transformed using lentivirus vectors with a chimeric antigen receptor, CAR.
• Usually involve the CDRs of a high-affinity antibody linked to a transmembrane region and a T-cell intracellular signaling molecule, one of the components of CD3.
  
  • Allows a transformed CTL to bind a tumor target with high affinity and chosen specificity, and, like an antibody, no MHC-restriction, and then be triggered via its normal TCR-associated pathway to become a fully-cytotoxic cell.
  • Used to treat lymphoma - prelim results are amazing

Question 8

Generally outline some of the ways in which a modified mAb could be used to diagnose or treat some forms of cancer

Answer 8

• A few mAb activate complement, and the tumor is lysed or phagocytosed
  
  • More often they invoke ADCC
• At least one mAb is available for use as both an imaging and a therapeutic drug, depending on which radioisotope is attached.

Question 9

Although Biological Response Modifiers (mAb’s are a type of BRM) are the cutting edge of modern medicine, there are still some big side effects associated with them.

1. Name 3 side effects of BRM’s (mAb’s)

Answer 9

1. All inherently toxic, some severely so
2. They can increase risk of cancer
3. Commonly increase risk of opportunistic infections

Question 10

What is a Bi-Specific T-cell engager ( BiTE)?

Answer 10

Researchers coupled together two single-chain engineered antibodies, one against CD19 and one against CD3.

• This construct can bind T cells via their CD3 to CD19+ of B cell lymphoma cells.
• The concept was named BiTE for Bispecific T-cell Engager. (Engages CTL)
• Use in Philadelphia-chromosome negative acute lymphoblastic leukemia (ALL)
  
  • Drug name: blinatumomab

*Bonus: do you remember what class the -omab is?